Previous quantitative Golgi studies have demonstrated age-related increases in dendritic extent in normal old human and animal brain but not in AD brain. In model regions that do not lose neurons with aging such age-related increase in dendritic extent is not found. We interpret these data as suggesting that neurons in the normal brain can respond to the age-related death of their neighbors with a plastic proliferation of additional dendritic material, and that this capacity is altered in AD. Model mechanisms that may aid in understanding this normal age- related dendritic proliferation include those that emphasize a glial response (probably astrocytic) to neuron death as providing trophic factor(s), while other models emphasize reduced competition for afferent supply consequent to the death of neighboring, competing neurons as allowing dendritic proliferation of the surviving neurons. We present preliminary data from human neocortex that indicate a positive relationship between numbers of glia and the extent of the dendritic neuropil (average dendritic extent per single neuron times the number of neurons of that type) in normal aging human brain and in late onset AD, but apparent breakdown of this relationship in early onset (long duration) AD. In this proposal we outline plans to capitalize on recent discoveries in protein correlates of neuronal growth and plasticity and also on the ability to differentially stain glial subtypes in postmortem human brain to confirm and extend our preliminary studies of the relationship between glia and the neuropil to test five hypotheses: (1) that the positive relationship between glia and neurites that has been shown by the in vitro work of others extends to the postmortem human brain, (2) that this relationship is disturbed in early onset (and/or long duration?) AD, (3) that the relationship is attributable largely to astrocytes, (4) that this relationship can be confirmed and extended to include axons by relating numbers of glia to levels of the neuronal growth associated protein, GAP-43, in postmortem human brain, and (5) start to test the hypothesis that the relationship between glia and dendritic neuropil is a function of age-related neuron death rather than being established during early development by dissecting the components of the dendritic tree into the early formed primary dendrites and the more recently formed terminal dendritic segments and examining the relationship of glia to the extent of each of these portions of the dendritic tree. These studies will also allow us to extend our hypotheses that there is residual neuronal plasticity in the normal aged human brain and that AD may be accompanied by diminished neuronal plasticity by using GAP-43 as an alternate measure of neuronal growth and plasticity.